The invention relates to compositions and methods for the treatment of proliferative disorders, including but not limited to cancer. The invention relates to the field of protecting normal cells and tissues from anticipated, planned or inadvertent exposure to ionizing radiation.
xcex1-xcex2-Unsaturated Sulfonamides
Cancer remains a leading cause of mortality in the United States and in the world. To be useful, a new chemotherapeutic agent should have a wide spectrum of activity and significant therapeutic index. Styrene-xcfx89-sulfonanilide has been prepared by reacting styrylsulfonyl chloride with aniline (Bordwell et al., J. Amer. Chem. Soc. 68:139, 1946). This and certain other styrene-xcfx89-sulfonanilides have been prepared by Knoevenagel-type synthesis as possible chemosterilants against the common house fly Musca domestica L. (Oliver et al, Synthesis 321-322, 1975).
U.S. Pat. No. 4,035,421 to Snyder, Jr. describes the preparation of N-(3,4-dichlorophenyl)-2-phenylethenesulfonamide and its use as an antibacterial agent.
The styrene-xcfx89-sulfonanilides 3xe2x80x2-hydroxy-4-nitrostyrene-xcex2-sulfonanilide, 3xe2x80x2-hydroxy-2-nitrostyrene-xcex2-sulfonanilide and 5xe2x80x2-hydroxy-2xe2x80x2-methyl-4-nitrostyrene-xcex2-sulfonanilide were utilized as intermediates in the preparation of certain stilbenes by Waldau et al. Angew. Chem., Int. Ed. Engl. 11(9):826-818 (1972). The styrene-xcfx89-sulfonanilides 3xe2x80x2-hydroxy-3-nitrostyrene-xcex2-sulfonanilide and 5xe2x80x2-hydroxy-2xe2x80x2-methyl-4-nitrostyrene-xcex2-sulfonanilide have been utilized in the preparation of stilbenes used as dyes (DE 2118493xe2x80x94Farbenfab AG).
Aswarthamma et al., Chimica Acta Turcica 24:7-10 (1996) disclose the preparation of certain trans-(1-aryl-(2-anilinesulphonyl)ethylenes. No biological activity is set forth for the compounds. Touarti et al., J. Soc. Alger. Chim. 6(1):39-52 (1996) disclose the preparation of certain xcex1,xcex2-unsaturated sulfonamides for inhibition of coniferyl alcohol dehydrogenase (CADH).
Except for the isolated teaching of antibacterial activity of N-(3,4-dichlorophenyl)-2-phenylethenesulfonamide, no useful pharmaceutical activity has been proposed for the limited numbers of xcex1,xcex2-unsaturated sulfonamides known to the prior art. In particular, no anti-cell proliferation or anticancer utility has been proposed for this class of compounds.
New cell antiproliferative agents, and anticancer therapeutics in particular, are needed which are useful in inhibiting proliferation of and/or killing cancer cells. In particular, such agents are needed which are selective in the killing of proliferating cells such as tumor cells, but not normal cells. Antineoplasitc agents are needed which are effective against a broad range of tumor types.
Ionizing Radiation Health Risks
Ionizing radiation has an adverse effect on cells and tissues, primarily through cytotoxic effects. In humans, exposure to ionizing radiation occurs primarily through therapeutic techniques (such as anticancer radiotherapy) or through occupational and environmental exposure.
A major source of exposure to ionizing radiation is the administration of therapeutic radiation in the treatment of cancer or other proliferative disorders. Depending on the course of treatment prescribed by the treating physician, multiple doses may be received by a subject over the course of several weeks to several months.
Therapeutic radiation is generally applied to a defined area of the subject""s body which contains abnormal proliferative tissue, in order to maximize the dose absorbed by the abnormal tissue and minimize the dose absorbed by the nearby normal tissue. However, it is difficult (if not impossible) to selectively administer therapeutic ionizing radiation to the abnormal tissue. Thus, normal tissue proximate to the abnormal tissue is also exposed to potentially damaging doses of ionizing radiation throughout the course of treatment. There are also some treatments that require exposure of the subject""s entire body to the radiation, in a procedure called xe2x80x9ctotal body irradiationxe2x80x9d, or xe2x80x9cTBI.xe2x80x9d The efficacy of radiotherapeutic techniques in destroying abnormal proliferative cells is therefore balanced by associated cytotoxic effects on nearby normal cells. Because of this, radiotherapy techniques have an inherently narrow therapeutic index which results in the inadequate treatment of most tumors. Even the best radiotherapeutic techniques may result in incomplete tumor reduction, tumor recurrence, increasing tumor burden, and induction of radiation resistant tumors.
Numerous methods have been designed to reduce normal tissue damage while still delivering effective therapeutic doses of ionizing radiation. These techniques include brachytherapy, fractionated and hyperfractionated dosing, complicated dose scheduling and delivery systems, and high voltage therapy with a linear accelerator. However, such techniques only attempt to strike a balance between the therapeutic and undesirable effects of the radiation, and full efficacy has not been achieved.
For example, one treatment for subjects with metastatic tumors involves harvesting their hematopoietic stem cells and then treating the subject with high doses of ionizing radiation. This treatment is designed to destroy the subject""s tumor cells, but has the side effect of also destroying their normal hematopoietic cells. Thus, a portion of the subject""s bone marrow (containing the hematopoietic stem cells), is removed prior to radiation therapy. Once the subject has been treated, the autologous hematopoietic stem cells are returned to their body.
However, if tumor cells have metastasized away from the tumor""s primary site, there is a high probability that some tumor cells will contaminate the harvested hematopoietic cell population. The harvested hematopoietic cell population may also contain neoplastic cells if the subject suffers from a cancers of the bone marrow such as the various French-American-British (FAB) subtypes of acute myelogenous leukemias (AML), chronic myeloid leukemia (CML), or acute lymphocytic leukemia (ALL). Thus, the metastasized tumor cells or resident neoplastic cells must be removed or killed prior to reintroducing the stem cells to the subject. If any living tumorigenic or neoplastic cells are reintroduced into the subject, they can lead to a relapse.
Prior art methods of removing tumorigenic or neoplastic cells from harvested bone marrow are based on a whole-population tumor cell separation or killing strategy, which typically does not kill or remove all of the contaminating malignant cells. Such methods include leukopheresis of mobilized peripheral blood cells, immunoaffinity-based selection or killing of tumor cells, or the use of cytotoxic or photosensitizing agents to selectively kill tumor cells. In the best case, the malignant cell burden may still be at 1 to 10 tumor cells for every 100,000 cells present in the initial harvest (Lazarus et al. J. of Hematotherapy, 2(4):457-66, 1993).
Thus, there is needed a purging method designed to selectively destroy the malignant cells present in the bone marrow, while preserving the normal hematopoietic stem cells needed for hematopoietic reconstitution in the transplantation subject.
Exposure to ionizing radiation can also occur in the occupational setting. Occupational doses of ionizing radiation may be received by persons whose job involves exposure (or potential exposure) to radiation, for example in the nuclear power and nuclear weapons industries. Military personnel stationed on vessels powered by nuclear reactors, or soldiers required to operate in areas contaminated by radioactive fallout, risk similar exposure to ionizing radiation. Occupational exposure may also occur in rescue and emergency personnel called in to deal with catastrophic events involving a nuclear reactor or radioactive material. Other sources of occupational exposure may be from machine parts, plastics, and solvents left over from the manufacture of radioactive medical products, smoke alarms, emergency signs, and other consumer goods. Occupational exposure may also occur in persons who serve on nuclear powered vessels, particularly those who tend the nuclear reactors, in military personnel operating in areas contaminated by nuclear weapons fallout, and in emergency personnel who deal with nuclear accidents. Environmental exposure to ionizing radiation may also result from nuclear weapons detonations (either experimental or during wartime), discharges of actinides from nuclear waste storage and processing and reprocessing of nuclear fuel, and from naturally occurring radioactive materials such as radon gas or uranium. There is also increasing concern that the use of ordnance containing depleted uranium results in low-level radioactive contamination of combat areas.
Radiation exposure from any source can be classified as acute (a single large exposure) or chronic (a series of small low-level, or continuous low-level exposures spread over time). Radiation sickness generally results from an acute exposure of a sufficient dose, and presents with a characteristic set of symptoms that appear in an orderly fashion, including hair loss, weakness, vomiting, diarrhea, skin bums and bleeding from the gastrointestinal tract and mucous membranes. Genetic defects, sterility and cancers (particularly bone marrow cancer) often develop over time. Chronic exposure is usually associated with delayed medical problems such as cancer and premature aging. An acute a total body exposure of 125,000 millirem may cause radiation sickness. Localized doses such as are used in radiotherapy may not cause radiation sickness, but may result in the damage or death of exposed normal cells.
For example, an acute total body radiation dose of 100,000-125,000 millirem (equivalent to 1 Gy) received in less than one week would result in observable physiologic effects such as skin bums or rashes, mucosal and GI bleeding, nausea, diarrhea and/or excessive fatigue. Longer term cytotoxic and genetic effects such as hematopoietic and immunocompetent cell destruction, hair loss (alopecia), gastrointestinal, and oral mucosal sloughing, venoocclusive disease of the liver and chronic vascular hyperplasia of cerebral vessels, cataracts, pneumonites, skin changes, and an increased incidence of cancer may also manifest over time. Acute doses of less than 10,000 millirem (equivalent to 0.1 Gy) typically will not result in immediately observable biologic or physiologic effects, although long term cytotoxic or genetic effects may occur.
A sufficiently large acute dose of ionizing radiation, for example 500,000 to over 1 million millirem (equivalent to 5-10 Gy), may kill a subject immediately. Doses in the hundreds of thousands of millirems may kill within 7 to 21 days from a condition called xe2x80x9cacute radiation poisoning.xe2x80x9d Reportedly, some of the Chernobyl firefighters died of acute radiation poisoning, having received acute doses in the range of 200,000-600,000 millirem (equivalent to 2-6 Gy). Acute doses below approximately 200,000 millirem do not result in death, but the exposed subject will likely suffer long-term cytotoxic or genetic effects as discussed above.
Acute occupational exposures usually occur in nuclear power plant workers exposed to accidental releases of radiation, or in fire and rescue personnel who respond to catastrophic events involving nuclear reactors or other sources of radioactive material. Suggested limits for acute occupational exposures in emergency situations were developed by the Brookhaven National Laboratories, and are given in Table 1.
A chronic dose is a low level (i.e., 100-5000 millirem) incremental or continuous radiation dose received over time. Examples of chronic doses include a whole body dose of xcx9c5000 millirem per year, which is the dose typically received by an adult working at a nuclear power plant. By contrast, the Atomic Energy Commission recommends that members of the general public should not receive more than 100 millirem per year. Chronic doses may cause long-term cytotoxic and genetic effects, for example manifesting as an increased risk of a radiation-induced cancer developing later in life. Recommended limits for chronic exposure to ionizing radiation are given in Table 2.
By way of comparison, Table 3 sets forth the radiation doses from common sources.
Chronic doses of greater than 5000 millirem per year (0.05 Gy per year) may result in long-term cytotoxic or genetic effects similar to those described for persons receiving acute doses. Some adverse cytotoxic or genetic effects may also occur at chronic doses of significantly less than 5000 millirem per year. For radiation protection purposes, it is assumed that any dose above zero can increase the risk of radiation-induced cancer (i.e., that there is no threshold). Epidemiologic studies have found that the estimated lifetime risk of dying from cancer is greater by about 0.04% per rem of radiation dose to the whole body.
While anti-radiation suits or other protective gear may be effective at reducing radiation exposure, such gear is expensive, unwieldy, and generally not available to public. Moreover, radioprotective gear will not protect normal tissue adjacent a tumor from stray radiation exposure during radiotherapy. What is needed, therefore, is a practical way to protect subjects who are scheduled to incur, or are at risk for incurring, exposure to ionizing radiation. In the context of therapeutic irradiation, it is desirable to enhance protection of normal cells while causing tumor cells to remain vulnerable to the detrimental effects of the radiation. Furthermore, it is desirable to provide systemic protection from anticipated or inadvertent total body irradiation, such as may occur with occupational or environmental exposures, or with certain therapeutic techniques.
Pharmaceutical radioprotectants offer a cost-efficient, effective and easily available alternative to radioprotective gear. However, previous attempts at radioprotection of normal cells with pharmaceutical compositions have not been entirely successful. For example, cytokines directed at mobilizing the peripheral blood progenitor cells confer a myeloprotective effect when given prior to radiation (Neta et al., Semin. Radiat. Oncol. 6:306-320, 1996), but do not confer systemic protection. Other chemical radioprotectors administered alone or in combination with biologic response modifiers have shown minor protective effects in mice, but application of these compounds to large mammals was less successful, and it was questioned whether chemical radioprotection was of any value (Maisin, J. R., Bacq and Alexander Award Lecture. xe2x80x9cChemical radioprotection: past, present, and future prospectsxe2x80x9d, Int J. Radiat Biol. 73:443-50, 1998). Pharmaceutical radiation sensitizers, which are known to preferentially enhance the effects of radiation in cancerous tissues, are clearly unsuited for the general systemic protection of normal tissues from exposure to ionizing radiation.
What is needed are therapeutic agents to protect subjects who have incurred, or are at risk for incurring exposure to ionizing radiation. In the context of therapeutic irradiation, it is desirable to enhance protection of normal cells while causing tumor cells to remain vulnerable to the detrimental effects of the radiation. Furthermore, it is desirable to provide systemic protection from anticipated or inadvertent total body irradiation, such as may occur with occupational or environmental exposures, or with certain therapeutic techniques.
It is an object of the invention to provide compounds, compositions and therapeutic methods. The biologically active compounds are in the form of N-(aryl)-2-arylethenesulfonamides, and pharmaceutically acceptable salts thereof.
It is an object of the invention to provide compounds, compositions and methods for the treatment of cancer and other proliferative diseases.
It is an object of the invention to provide compounds which are selective in killing tumor cells but not normal cells.
It is an object of the invention to provide compounds, compositions and methods for inducing neoplastic cells to selectively undergo apoptosis.
It is an object of the invention to provide compounds, compositions and methods for protecting normal cells and tissues from the cytotoxic and genetic effects of exposure to ionizing radiation, in subjects who have incurred or are at risk for incurring exposure to ionizing radiation. The exposure to ionizing radiation may occur in controlled doses during the treatment of cancer and other proliferative disorders, or may occur in uncontrolled doses beyond the norm accepted for the population at large during high risk activities or environmental exposures.
In another aspect, a method of treating a subject for cancer or other proliferative disorders is provided, comprising administering to the subject an effective amount of at least one radioprotectant N-(aryl)-2-arylethenesulfonamide compound prior to administering an effective amount of ionizing radiation, wherein the radioprotective N-(aryl)-2-arylethenesulfonamide compound induces a temporary radioresistant phenotype in the subject""s normal tissue.
In a further aspect, the invention provides a method of safely increasing the dosage of therapeutic ionizing radiation used in the treatment of cancer or other proliferative disorders, comprising administering an effective amount of at least one radioprotective N-(aryl)-2-arylethenesulfonamide compound prior to administration of the therapeutic ionizing radiation, which radioprotective compound induces a temporary radioresistant phenotype in the subject""s normal tissue.
In yet a further aspect, the invention provides a method for treating individuals who have incurred or are at risk for incurring remediable radiation damage from exposure to ionizing radiation. In one embodiment, an effective amount of at least one radioprotective N-(aryl)-2-arylethenesulfonamide compound is administered to the subject before the subject incurs remediable radiation damage from exposure to ionizing radiation. In another embodiment, an effective amount of at least one radioprotective N-(aryl)-2-arylethenesulfonamide compound is administered to the subject after the subject incurs remediable radiation damage from exposure to ionizing radiation.
In yet another embodiment, the invention provides a method for purging bone marrow of neoplastic cells (such as leukemic cells) or tumor cells which have metastasized into the bone marrow, comprising harvesting bone marrow cells from an individual afflicted with a proliferative disorder, treating the harvested bone marrow cells with an effective amount of at least one N-(aryl)-2-arylethenesulfonamide compound, and subjecting the treated bone marrow cells to an effective amount of ionizing radiation. The harvested cells are then returned to the body of the afflicted individual.
In another aspect, the invention is directed to novel compounds of formula I: 
wherein:
Q1, and Q2 are independently selected from the group consisting of substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl;
R is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)alkenyl, (C2-C6)heteroalkyl, (C3-C6)heteroalkenyl, (C2-C6)hydroxyalkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted aryl(C1-C3)alkyl, unsubstituted aryl(C1-C3)alkyl, substituted heteroaryl(C1-C3)alkyl and unsubstituted heteroaryl(C1-C3)alkyl;
wherein the substituents for the substituted aryl and substituted heteroaryl groups comprising Q1 are independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano, carboxy, carboxy(C1-C3)alkoxy, hydroxy, (C2-C6)hydroxyalkyl, phosphonato, amino, (C1-C6)acylamino, sulfamyl, acetoxy, di(C1-C6)alkylamino(C2-C6 alkoxy), trifluoromethyl and
wherein the substituents for the substituted aryl and substituted heteroaryl groups comprising Q1, are independently selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, nitro, cyano, carboxy, carboxy(C1-C3)alkoxy, hydroxy, (C2-C6)hydroxyalkyl, phosphonato, amino, (C1-C6)acylamino, sulfamyl, acetoxy, di(C1 -C6)alkylamino(C2-C6)alkoxy, trifluoromethyl and 
xe2x80x83wherein:
X is oxygen or sulfur,
R5 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)heteroalkyl, substituted phenyl and unsubstituted phenyl, and
R6 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)heteroalkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted aryl-(C1-C3)alkyl, unsubstituted aryl-(C1-C3)alkyl and (C1-C6)alkoxycarbonyl(C1-C6)alkylenyl; and
wherein the substituents for the substituted aryl and substituted heteroaryl groups comprising Q2, and the substituents for the substituted aryl and substituted heteroaryl groups comprising or included within R, R5 and R6, are independently selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, nitro, cyano, carboxy, carboxy(C1-C3)alkoxy, hydroxy, (C2-C6)hydroxyalkyl, phosphonato, amino, (C1-C6)acylamino, sulfamyl, acetoxy, di(C1-C6)alkylamino(C2-C6)alkoxy and trifluoromethyl;
provided, that when R is hydrogen:
(a) when Q1 is unsubstituted phenyl, Q2 is other than dimethoxyphenyl, 2-methylphenyl, 2-chlorophenyl, 4-chlorophenyl, 4-N,N-dimethylaminophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-nitrophenyl, 3-methoxy-4-hydroxyphenyl, unsubstituted phenyl, unsubstituted phenyl, unsubstituted benzodioxolyl, unsubstituted 1-naphthyl and unsubstituted 2-thienyl; in a sub-embodiment, when Q1 is unsubstituted phenyl, Q2 is other than dialkoxyphenyl, 2-alkylphenyl, 2-halophenyl, 4-halophenyl, 4-N,N-dialkylaminophenyl, 4-alkylphenyl, 4-alkoxyphenyl, 4-nitrophenyl, 3-alkoxy-4-hydroxyphenyl, unsubstituted phenyl, unsubstituted phenyl, unsubstituted benzodioxolyl, unsubstituted 1-naphthyl and unsubstituted 2-thienyl;
(b) when Q1 is 2,4-dinitrophenyl, Q2 is other than 4-methylphenyl, 4-methoxyphenyl, 4-nitrophenyl, 4-bromophenyl, 3,4-dichlorophenyl, unsubstituted phenyl or unsubstituted 1-naphthyl; in a sub-embodiment, when Q1 is 2,4-dinitrophenyl, Q2 is other than 4-alkylphenyl, 4-alkoxyphenyl, 4-nitrophenyl, 4-halophenyl, 3,4-dihalophenyl, unsubstituted phenyl or unsubstituted 1-naphthyl;
(c) when Q1 is 3-hydroxyphenyl, Q2 is other than 2-nitrophenyl, or 3-nitrophenyl; in a sub-embodiment, when Q1 is 3-hydroxyphenyl, Q2 is other than nitrophenyl;
(d) when Q1 is 2-methyl-5-hydroxyphenyl, Q2 is other than 4-nitrophenyl; in a sub-embodiment, when Q1 is 2-methyl-5-hydroxyphenyl, Q2 is other than 4-nitrophenyl;
(e) when Q1 is unsubstituted 2-pyridyl, Q2 is other than 3-methoxy-4-hydroxyphenyl; in a sub-embodiment, when Q1 is unsubstituted 2-pyridyl, Q2 is other than 3-methoxy-4-hydroxyphenyl; and
(f) when Q2 is unsubstituted phenyl, Q1 is other than 2-hydroxyphenyl, 2-aminophenyl, 3,4-dichlorophenyl or unsubstituted 2-pyridyl; in a sub-embodiment, when Q2 is unsubstituted phenyl, Q1 is other than 2-hydroxyphenyl, 2-aminophenyl, 3,4-dihalophenyl or unsubstituted 2-pyridyl; or a pharmaceutically acceptable salt thereof.
In a further sub-embodiment, novel compounds of formula I are provided wherein Q1 and Q2 are independently selected from the group consisting of substituted aryl and substituted heteroaryl; R is defined as above; the substituents for the substituted aryl and substituted heteroaryl groups comprising Q1 are defined as above; the substituents for the substituted aryl and substituted heteroaryl groups comprising Q2, and the substituents for the substituted aryl and substituted heteroaryl groups comprising or included within R, R5 and R6, are defined as above,
provided, when R is hydrogen:
(i) Q1 may not be dinitrophenyl;
(ii) Q2 may not be dinitrophenyl; and
(iii) when Q2 is mononitrophenyl:
Q1 is other than substituted phenyl, or
Q1 is substituted phenyl wherein at least the 4-position is substituted, and the substituent is other than hydroxy;
or a pharmaceutically acceptable salt thereof.
According to another embodiment, the invention is directed to a process for preparing a novel compound as defined above, the process comprising reacting a compound of the formula B: 
with a compound of the formula C 
in a nonprotic solvent in the presence of a base to form a compound of the formula: 
wherein R, Q1 and Q2 are defined as above. Compound B may be prepared by reacting a compound of the formula A, Q2xe2x80x94CHxe2x95x90CH2, with sulfonyl chloride in the presence of a nonprotic solvent.
According to another embodiment, the invention is directed to an alternative process for preparing a novel compound as defined above, said process comprising reacting a compound of the formula G 
with a compound of the formula H 
in the presence of a basic catalyst to form a compound of the formula: 
wherein R, Q1 and Q2 are defined as above.
Compounds of formula G may be prepared by reacting a compound of the formula E, ClSO2xe2x80x94CH2xe2x80x94C(O)ORxe2x80x2, with a compound of formula C (as defined above) in a nonprotic solvent in the presence of a base to form a compound of the formula F, 
and then treating the formula F compound with a base capable of hydrolyzing the ester function thereof to an acid to form compound G; wherein R and Q1 are defined as above, and Rxe2x80x2 is methyl or ethyl.
According to another embodiment of the invention, pharmaceutical compositions are provided comprising a pharmaceutically acceptable carrier and a compound according to formula I wherein
Q1 and Q2 are independently selected from the group consisting of substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl; and R is defined as above;
wherein the substituents for the substituted aryl and substituted heteroaryl groups comprising Q1 are independently selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, nitro, cyano, carboxy, carboxy(C1-C3)alkoxy, hydroxy, (C2-C6)hydroxyalkyl, phosphonato, amino, (C1-C6)acylamino, sulfamyl, acetoxy, di(C1-C6)alkylamino(C2-C6)alkoxy, trifluoromethyl and 
xe2x80x83wherein:
X is oxygen or sulfur,
R5 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)heteroalkyl, substituted phenyl and unsubstituted phenyl, and
R6 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)heteroalkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted aryl-(C1-C3)alkyl, unsubstituted aryl-(C1-C3)alkyl and (C1-C6)alkoxycarbonyl(C1-C6)alkylenyl; and
wherein the substituents for the substituted aryl and substituted heteroaryl groups comprising Q2, and the substituents for the substituted aryl and substituted heteroaryl groups comprising or included within R, R5 and R6, are independently selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, nitro, cyano, carboxy, carboxy(C1-C3)alkoxy, hydroxy, (C2-C6)hydroxyalkyl, phosphonato, amino, (C1-C6)acylamino, sulfamyl, acetoxy, di(C1-C6)alkylamino(C2-C6)alkoxy and trifluoromethyl;
provided, when R is hydrogen and Q2 is unsubstituted phenyl, then Q1 must be other than 3,4-dichlorophenyl, more particularly other than 3,4-dihalophenyl, even more particularly other than dihalophenyl;
or a pharmaceutically acceptable salt thereof.
According to another embodiment of the invention, a method of treating an individual for a proliferative disorder comprises administering to said individual an effective amount of at least one N-(aryl)-2-arylethenesulfonamide compound.
According to another embodiment of the invention, a method of inducing apoptosis of tumor cells in an individual afflicted with cancer is provided, comprising administering to said individual an effective amount of at least one N-(aryl)-2-arylethenesulfonamide compound.
According to another embodiment of the invention, a method of reducing or eliminating the effects of ionizing radiation on normal cells in a subject who has incurred or is at risk for incurring exposure to ionizing radiation is provided. An effective amount of at least one N-(aryl)-2-arylethenesulfonamide compound is administered to the subject prior to or after exposure to ionizing radiation.
A method of safely increasing the dosage of therapeutic ionizing radiation used in the treatment of cancer or other proliferative disorders is also provided. The method comprises administering an effective amount of at least one radioprotective N-(aryl)-2-arylethenesulfonamide compound prior to administration of the therapeutic ionizing radiation, which radioprotective compound induces a temporary radioresistant phenotype in the normal tissue of the subject.
A method for treating a subject who has incurred or is at risk for incurring remediable radiation damage from exposure to ionizing radiation comprises administering an effective amount of at least one radioprotective N-(aryl)-2-arylethenesulfonamide compound prior to or after incurring remedial radiation damage from exposure to ionizing radiation.
For all of the aforementioned therapeutic methods, the administered compound is a compound according to formula I wherein:
Q1 and Q2 are independently selected from the group consisting of substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl;
R is defined as above;
wherein the substituents for the substituted aryl and substituted heteroaryl groups comprising Q1 are independently selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, nitro, cyano, carboxy, carboxy(C1-C3)alkoxy, hydroxy, (C2-C6)hydroxyalkyl, phosphonato, amino, (C1-C6)acylamino, sulfamyl, acetoxy, di(C1-C6)alkylamino(C2-C6)alkoxy, trifluoromethyl and 
xe2x80x83wherein:
X is oxygen or sulfur,
R5 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)heteroalkyl, substituted phenyl and unsubstituted phenyl, and
R6 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)heteroalkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted aryl-(C1-C3)alkyl, unsubstituted aryl-(C1-C3)alkyl and (C1-C6)alkoxycarbonyl(C1-C6)alkylenyl; and
wherein the substituents for the substituted aryl and substituted heteroaryl groups comprising Q2, and the substituents for the substituted aryl and substituted heteroaryl groups comprising or included within R, R5 and R6, are independently selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, nitro, cyano, carboxy, carboxy(C1-C3)alkoxy, hydroxy, (C2-C6)hydroxyalkyl, phosphonato, amino, (C1-C6)acylamino, sulfamyl, acetoxy, di(C1-C6)alkylamino(C2-C6)alkoxy and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
The term xe2x80x9cacylxe2x80x9d means a radical of the general formula xe2x80x94C(xe2x95x90O)xe2x80x94R, wherein xe2x80x94R is hydrogen, hydrocarbyl, amino or alkoxy. Examples include for example, acetyl (xe2x80x94C(xe2x95x90O)CH3), propionyl (xe2x80x94C(xe2x95x90O)CH2CH3), benzoyl (xe2x80x94C(xe2x95x90O)C6H5). Phenylacetyl (xe2x80x94C(xe2x95x90O)CH2C6H5), carboethoxy (xe2x80x94CO2Et), and dimethylcarbamoyl (xe2x80x94C(xe2x95x90O)N(CH3)2).
The term xe2x80x9caromaticxe2x80x9d refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (4n+2) delocalized xcfx80(pi) electrons).
The term xe2x80x9c(C2-C6)acylaminoxe2x80x9d means a radical containing a two to six carbon straight or branched chain acyl group attached to a nitrogen atom via the acyl carbonyl carbon. Examples include xe2x80x94NHC(O)CH2CH2CH3 and xe2x80x94NHC(O)CH2CH2 CH2CH2CH3.
The term xe2x80x9calkylxe2x80x9d, by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon radical, including di- and multi-radicals, having the number of carbon atoms designated (i.e. (C1-C6) means one to six carbons) and includes straight or branched chain groups. Most preferred is (C1-C3)alkyl, ethyl or methyl.
The term xe2x80x9calkoxyxe2x80x9d employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy and the higher homologs and isomers. Preferred are (C1-C3)alkoxy, ethoxy or methoxy.
The term xe2x80x9calkylenylxe2x80x9d by itself or as part of another substituent means a divalent radical derived from a straight or branched chain alkane having the indicated number of carbon atoms, as exemplified by the four-carbon radical xe2x80x94CH2CH2CH2CH2xe2x80x94.
The term xe2x80x9calkenylxe2x80x9d employed alone or in combination with other terms, means, unless otherwise stated, a stable straight chain or branched monounsaturated or diunsaturated hydrocarbon group having the stated number of carbon atoms. Examples include vinyl, propenyl (allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and the higher homologs and isomers. A divalent radical derived from an alkene is exemplified by xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94.
The term xe2x80x9ccarboxy(C1-C3)alkoxyxe2x80x9d means a radical in which the carboxy group xe2x80x94COOH is attached to a carbon of a straight or branched chain alkoxy group containing one to three carbon atoms. The radical thus contains up to four carbon atoms. Examples include HOC(O)CH2CH2CH2Oxe2x80x94 and HOC(O)CH2CH2Oxe2x80x94.
The term xe2x80x9cheteroalkylxe2x80x9d by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain radical consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2CH2xe2x80x94OH, xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94CH3, xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94CH3, and xe2x80x94CH2CH2xe2x80x94S(O)xe2x80x94CH3. Up to two heteroatoms may be consecutive, such as, for example, xe2x80x94CH2xe2x80x94NHxe2x80x94OCH3.
The term xe2x80x9cheteroalkenylxe2x80x9d by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated or diunsaturated hydrocarbon radical consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively. Examples include xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94CH3, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94OH, xe2x80x94CH2xe2x80x94CHxe2x95x90Nxe2x80x94OCH3, xe2x80x94CHxe2x95x90CHxe2x80x94N(CH3)xe2x80x94CH3, and xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94SH.
The term xe2x80x9chydroxyalkylxe2x80x9d means an alkyl radical wherein one or more of the carbon atoms is substituted with hydroxy. Examples include xe2x80x94CH2CH(OH)CH3 and xe2x80x94CH2CH2OH. The terms xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
The term xe2x80x9c(C1-C6)alkoxycarbonyl(C1-C6)alkylenylxe2x80x9d means a group of the formula CH3(CH2)pOC(O)(CH2)qxe2x80x94 wherein p is an integer from zero to five and q is an integer from one to six.
The term xe2x80x9cdi(C1-C6)alkylamino(C2-C6)alkoxyxe2x80x9d means (alkyl)2N(CH2)nOxe2x80x94 wherein the two alkyl chains connected to the nitrogen atom independently contain from one to six carbon atoms, preferably from one to three carbon atoms, and n is an integer from 2 to 6. Preferably, n is 2 or 3. Most preferably, n is 2, and the alkyl groups are methyl, that is, the group is the dimethylaminoethoxy group, (CH3)2NCH2CH2Oxe2x80x94.
The term xe2x80x9cphosphonatoxe2x80x9d means the group xe2x80x94PO(OH)2.
The term xe2x80x9csulfamylxe2x80x9d means the group xe2x80x94SO2NH2.
The term xe2x80x9carylxe2x80x9d employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be attached together in a pendent manner or may be fused. Examples include phenyl; anthracyl; and naphthyl, particularly1-naphthyl and 2-naphthyl.
The term xe2x80x9caryl-(C1-C3)alkylxe2x80x9d means a radical wherein a one to three carbon alkylene chain is attached to an aryl group, e.g., xe2x80x94CH2CH2-phenyl. Similarly, the term xe2x80x9cheteroaryl-(C1-C3)alkylxe2x80x9d means a radical wherein a one to three carbon alkylene chain is attached to a heteroaryl group, e.g., xe2x80x94CH2CH2-pyridyl. The term xe2x80x9csubstituted aryl-(C1-C3)alkylxe2x80x9d means an aryl-(C1-C3)alky radical in which the aryl group is substituted. The term xe2x80x9csubstituted heteroaryl-(C1-C3)alkylxe2x80x9d means a heteroaryl-(C1-C3)alky radical in which the heteroaryl group is substituted.
The term xe2x80x9cheteroarylxe2x80x9d by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted, stable, mono- or multicyclic heterocyclic aromatic ring system which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom which affords a stable structure.
Examples of such heteroaryls include benzimidazolyl, particularly 2-benzimidazolyl; benzofuryl, particularly 3-, 4-, 5-, 6- and 7-benzofuryl; 2-benzothiazolyl and 5-benzothiazolyl; benzothienyl, particularly 3-, 4-, 5-, 6-, and 7-benzothienyl; 4-(2-benzyloxazolyl); furyl, particularly 2- and 3-furyl; isoquinolyl, particularly 1- and 5-isoquinolyl; isoxazolyl, particularly 3-, 4- and 5-isoxazolyl; imidazolyl, particularly 2-, -4 and 5-imidazolyl; indolyl, particularly 3-, 4-, 5-, 6- and 7-indolyl; oxazolyl, particularly 2-, 4- and 5-oxazolyl; purinyl; pyrrolyl, particularly 2-pyrrolyl, 3-pyrrolyl; pyrazolyl, particularly 3- and 5-pyrazolyl; pyrazinyl, particularly 2-pyrazinyl; pyridazinyl, particularly 3- and 4-pyridazinyl; pyridyl, particularly 2-, 3- and 4-pyridyl; pyrimidinyl, particularly 2- and 4-pyrimidyl; quinoxalinyl, particularly 2- and 5-quinoxalinyl; quinolinyl, particularly 2- and 3-quinolinyl; 5-tetrazolyl; thiazolyl; particularly 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; thienyl, particularly 2- and 3-thienyl; and 3-(1,2,4-triazolyl). The aforementioned listing of heteroaryl moieties is intended to be representative, not limiting. In another embodiment of the invention, Q1 is independently selected from the group consisting of substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, provided that Q1, is not 2-thiazolyl. In a further embodiment of the invention, Q1 is independently selected from the group consisting of substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, provided that Q1 is not 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.
The term xe2x80x9csubstitutedxe2x80x9d means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group. For aryl and heteroaryl groups, the xe2x80x9csubstitutedxe2x80x9d is meant any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution. The substituents are independently selected.
For purposes of this disclosure, the term aryl in the expression xe2x80x9cN-(aryl)-2-arylethenesulfonamidexe2x80x9d is deemed to include both xe2x80x9carylxe2x80x9d and xe2x80x9cheteroarylxe2x80x9d radicals, either substituted or unsubstituted, unless otherwise indicated.
The term xe2x80x9csubjectxe2x80x9d or xe2x80x9cindividualxe2x80x9d includes human beings and non-human animals. With respect to the disclosed radioprotective methods, these terms further refer to an organism which is scheduled to incur, is at risk for incurring, or has incurred, exposure to ionizing radiation.
As used herein, xe2x80x9cionizing radiationxe2x80x9d is radiation of sufficient energy that, when absorbed by cells and tissues, induces formation of reactive oxygen species and DNA damage. This type of radiation includes X-rays, gamma rays, and particle bombardment (e.g., neutron beam, electron beam, protons, mesons and others), and is used for medical testing and treatment, scientific purposes, industrial testing, manufacturing and sterilization, weapons and weapons development, and many other uses. Radiation is typically measured in units of absorbed dose, such as the rad or gray (Gy), or in units of dose equivalence, such as the rem or sievert (Sv). The relationship between these units is given below:
The Sv is the Gy dosage multiplied by a factor that includes tissue damage done. For example, penetrating ionizing radiation (e.g., gamma and beta radiation) have a factor of about 1, so 1 Sv=xcx9c1 Gy. Alpha rays have a factor of 20, so 1 Gy of alpha radiation=20 Sv.
By xe2x80x9ceffective amount of ionizing radiationxe2x80x9d is meant an amount of ionizing radiation effective in killing, or reducing the proliferation, of abnormally proliferating cells in a subject. As used with respect to bone marrow purging, xe2x80x9ceffective amount of ionizing radiationxe2x80x9d means an amount of ionizing radiation effective in killing, or in reducing the proliferation, of malignant cells in a bone marrow sample removed from a subject.
By xe2x80x9cacute exposure to ionizing radiationxe2x80x9d or xe2x80x9cacute dose of ionizing radiationxe2x80x9d is meant a dose of ionizing radiation absorbed by a subject in less than 24 hours. The acute dose may be localized, as in radiotherapy techniques, or may be absorbed by the subjects entire body. Acute doses are typically above 10,000 millirem (0.1 Gy), but may be lower.
By xe2x80x9cchronic exposure to ionizing radiationxe2x80x9d or xe2x80x9cchronic dose of ionizing radiationxe2x80x9d is meant a dose of ionizing radiation absorbed by a subject over a period greater than 24 hours. The dose may be intermittent or continuous, and may be localized or absorbed by the subject""s entire body. Chronic doses are typically less than 10,000 millirem (0.1 Gy), but may be higher.
By xe2x80x9ceffective amount of radioprotective N-(aryl)-2-arylethenesulfonamide compoundxe2x80x9d is meant an amount of compound effective to reduce or eliminate the toxicity associated with radiation in normal cells of the subject, and also to impart a direct cytotoxic effect to abnormally proliferating cells in the subject. As used with respect to bone marrow purging, xe2x80x9ceffective amount of the radioprotective N-(aryl)-2-arylethenesulfonamide compoundxe2x80x9d means an amount of compound effective to reduce or eliminate the toxicity associated with radiation in bone marrow removed from a subject, and also to impart a direct cytotoxic effect to malignant cells in the bone marrow removed from the subject.
By xe2x80x9cat risk of incurring exposure to ionizing radiationxe2x80x9d is meant that a subject may advertently (such as by scheduled radiotherapy sessions) or inadvertently be exposed to ionizing radiation in the future. Inadvertent exposure includes accidental or unplanned environmental or occupational exposure.